 |
PDBsum entry 1s1n
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Cell adhesion
|
PDB id
|
|
|
|
1s1n
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Solution nmr structure of the sh3 domain of human nephrocystin and analysis of a mutation-Causing juvenile nephronophthisis.
|
|
|
Authors
|
|
A.Le maire,
T.Weber,
S.Saunier,
I.Broutin,
C.Antignac,
A.Ducruix,
F.Dardel.
|
|
|
Ref.
|
|
Proteins, 2005,
59,
347-355.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Human nephrocystin is a protein associated with juvenile NPH, an autosomal
recessive, inherited kidney disease responsible for chronic renal failure in
children. It contains an SH3 domain involved in signaling pathways controlling
cell adhesion and cytoskeleton organization. The solution structure of this
domain was solved by triple resonance NMR spectroscopy. Within the core, the
structure is similar to those previously reported for other SH3 domains but
exhibits a number of specific noncanonical features within the polyproline
ligand binding site. Some of the key conserved residues are missing, and the
N-Src loop exhibits an unusual twisted geometry, which results in a narrowing of
the binding groove. This is induced by the replacement of a conserved Asp, Asn,
or Glu residue by a Pro at one side of the N-Src loop. A systematic survey of
other SH3 domains also containing a Pro at this position reveals that most of
them belong to proteins involved in cell adhesion or motility. A variant of this
domain, which carries a point mutation causing NPH, was also analyzed. This
change, L180P, although it corresponds to a nonconserved and solvent-exposed
position, causes a complete loss of the tertiary structure. Similar effects are
also observed with the L180A variant. This could be a context-dependent effect
resulting from an interaction between neighboring charged side-chains.
|
|
|
|
|
|
|
|
Figure 3.
Figure 3. The N-src loop of nephrocystin SH3 is twisted by a
noncanonical proline residue. Stereo view of the superimposed
backbones of nephrocystin (green) and N-Crk SH3 (yellow; PDB
entry: 1CKA). The two structures are very similar, with the
exception of the N-Src loop, at the right. Proline 186, which
induces a kink in nephrocystin, is shown in red. It corresponds
to a position where a semiconserved Glu, Asp, or Asn residue is
found in most SH3 domains.
|
|
Figure 5.
Figure 5. Destabilization of the SH3 fold by the L180
mutations. (Left) Sructure of the wild-type nephrocystin SH3.
The side-chains of E156, L180, and K193 are indicated. (Right)
Model of the mutant L180P structure. The diverging type II  -turn,
which folds independently in solution is highligthed in yellow.
After the MD simulation, the major structural change was the
movement of E156 and K193 side-chains, the terminal atoms of
which come in Van der Waals contact over the pyrrolidine ring of
P180 (right). This also induced a partial disruption of the
underlying -sheet
structure.
|
|
|
|
|
|
The above figures are
reprinted
by permission from John Wiley & Sons, Inc.:
Proteins
(2005,
59,
347-355)
copyright 2005.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
A novel gene that encodes a protein with a putative src homology 3 domain is a candidate gene for familial juvenile nephronophthisis.
|
|
|
Authors
|
|
S.Saunier,
J.Calado,
R.Heilig,
F.Silbermann,
F.Benessy,
G.Morin,
M.Konrad,
M.Broyer,
M.C.Gubler,
J.Weissenbach,
C.Antignac.
|
|
|
Ref.
|
|
Hum Mol Genet, 1997,
6,
2317-2323.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Secondary reference #2
|
|
|
Title
|
|
A novel gene encoding an sh3 domain protein is mutated in nephronophthisis type 1.
|
|
|
Authors
|
|
F.Hildebrandt,
E.Otto,
C.Rensing,
H.G.Nothwang,
M.Vollmer,
J.Adolphs,
H.Hanusch,
M.Brandis.
|
|
|
Ref.
|
|
Nat Genet, 1997,
17,
149-153.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
